Citric acid cycle scheme

In contrast, selective inhibition of enzyme activity involves highly specific interactions between the protein and chemical groups on the xenobiotic. An excellent example of this type of inhibition is seen in the toxic effect of fluoroacetate, which is used as a rodenticide. Although fluoroacetate is not directly toxic, it is metabolized to fluoroacetyl-CoA, which enters the citric acid cycle due to its structural similarity to acetyl-CoA (Scheme 3.5). Within the cycle, fluoroacetyl-CoA combines with oxalo-acetate to form fluorocitrate, which inhibits the next enzyme, aconitase, in the cycle [42]. The enzyme is unable to catalyze the dehydration to cis-aconitate, as a consequence of the stronger C-F bond compared with the C-H bond. Therefore, fluorocitrate acts as a pseudosubstrate, which blocks the citric acid cycle and, subsequently, impairs ATP synthesis. 

Figure 20-8 Perspective of the metabolic scheme whereby carbohydrates, fats, and proteins in foodstuffs are oxidized to C02, showing the link between glycolysis, the citric acid cycle, and oxidative phosphorylation...

Synthesizing a-ketoglutarate. It is possible, with the use of the reactions and enzymes discussed in this chapter, to convert pyruvate into a-ketoglutarate without depleting any of the citric acid cycle components. Write a balanced reaction scheme for this conversion, showing cofactors and identifying the required enzymes. 

From the scheme proposed for Tp. acidophilum, there is no net yield of ATP during the oxidation of glucose to pyruvate. As will be discussed later, the citric acid cycle is probably operational and will produce ATP. However, acetate is excreted from this archaebacterium during growth on glucose[15], and we have shown[2,16] that it is generated from acetyl-CoA with the concomitant production of ATP via the enzyme acetyl-CoA synthase (ADP utilising) ... 

The reaction Eq. (32) proceeds via a sequence of steps catalyzed by a multi-enzyme system. Because of the chemical nature of the primary acceptor of active acetic acid the sequence is referred to as citric acid cycle , firstly postulated 1937 by Krebs207. The reaction scheme is depicted in Fig. 1. 

A compound that is especially easy to observe is glutamate. This amino acid, most of which is found in the cytoplasm, is nevertheless in relatively rapid equilibrium with 2-oxoglutarate of the citric acid cycle in the mitochondria. The accompanying scheme shows where isotopic carbon from certain compounds will be located when it first enters the citric acid cycle and traces some of the labels into glutamate. For example, uniformly enriched fatty acids will introduce label into the two atoms of the pro-S arm of citrate and into 4- and 5-positions of glutamate whereas [2- C]acetate will introduce label only into the C4 position as marked by in the scheme. In the NMR spectrum a singlet resonance at 32.4 ppm will be observed. However, as successive turns of the citric acid cycle occur the isotope will appear in increasing amounts in the adjacent... 

Figure 19.10 shows schematically the various catabolic pathways that feed into the citric acid cycle. The catabolic reactions occur in the cytosol the citric acid cycle takes place in mitochondria. Many of the end products of catabolism cross the mitochondrial membrane and then participate in the citric acid cycle. This figure also shows the outline of pathways by which amino acids are converted to components of the citric acid cycle. Be sure to notice that sugars, fatty acids, and amino acids are all included in this overall catabolic scheme. Just as all roads lead to Rome, all pathways lead to the citric acid cycle. 

If the methyl carbon atom of pyruvate is labeled with which of the carbon atoms of oxaloacetate would be labeled after one turn of the citric acid cycle (See the lettering scheme for oxaloacetate in Figure 17.1 in this book.) Note that the new acetate carbons are the two shown at the bottom of the first few structures in the cycle, because aconitase reacts stereospecifically. 

In the early 1900s, Thunberg proposed a cyclic pathway for the oxidation of acetate. In his scheme, two molecules of acetate are condensed, with reduction, to form succinate, which in turn is oxidized to yield oxaloacetate. The decarboxylation of oxaloacetate to pyruvate followed by the oxidative decarboxylation of pyruvate to acetate complete the cycle. Assuming that electron carriers like NAD" and FAD would be part of the scheme, compare the energy liberated by the Thunberg scheme with that liberated by the now-established citric acid cycle. Which of the steps in Thunberg s scheme was not found in subsequent studies ... 

Fig. 2.3 Proposed scheme of the metabohc side of HIF-1 regulation through ketosis. The inhibition of the PHD reaction by an intermediate of energy metabolism, succinate, as a result of ketone body utilization by brain. The relationship of the metabolic pathways of glucose and ketone bodies entering the citric acid cycle and HlF-1 is illustrated. In contrast to glucose metabolism, increased ketone metabolism results in elevated levels of mitochondrial succinate, which is transported out of the mitochondria into the cytosol resulting in the inhibition of PHD and thus stabilization of HIF-1...

Deamination of amino acids in animal tissue is generally effected by transamination with an a-keto-acid. In the majority of cases, this is 2-oxoglutarate formed by the citric acid cycle. Aspartate aminotransferase and alanine aminotransferase are examples of this kind of reaction. In Figure 2.7, transamination involving these enzymes is depicted as it is known to occur in mammalian liver. Note that the scheme shown here requires participation of oxalacetate and pyruvate and thus is intimately connected with metabolic pathways considered earlier. Serine and glycine are readily interconvertible in animal tissue by the enzyme serine hydroxymethyltransferase. It is worth noting also that decarboxylation of serine to ethanolamine as mentioned above can be followed by A -methylation to yield choline. Choline is both an essential component of many... 

The Citric Acid Cycle (or the Tricarboxylic Acid [TCA] Cycle or the Krebsi Cycle). It will be recalled (Schemes 11.24-11.26) that the enzyme phosphoglycerate mutase (EC 5.4.2.1) acts on PGA (obtained from, e.g., fructose-1,6-bisphosphate) to produce the isomeric, 2-phosphoglycerate and that phosphopyruvate hydratase (EC 4.2.1.11) then converts the 2-phosphoglycerate to phosphoenolpyruvate. 

In addition to polyketides and mevalonic acid-derived species, acetyl-CoA moves through the TCA (or the citric acid cycle, or the Krebs cycle), a cycle (which by dehnition cannot have a beginning or end) that serves to produce many useful fragments as well as to effect the complete oxidation of pyruvic acid. As shown in Scheme 11.89, as acetyl-CoA enters the already turning cycle, an addition to the carbonyl group of oxaloacetate occurs (citrate synthase, EC 2.3.3.1) to produce citrate. In the addition process, the methyl group of the acetyl-CoA becomes the pw-S carbon in citrate. 

In the presence of fumarase (fumarate hydratase, EC 4.2.12) malate undergoes reversible dehydration to generate fumarate (citric acid cycle). In this process (a franx-elimination), the hydroxyl at C-2 and the pro-R hydrogen at C-3 are lost (Scheme 13.23). 

The nature of the major C-labeled isoptomers of intermediates formed by consecutive turns of the citric acid cycle are illustrated in Figure 5A for condensation of various labeled oxalacetate species with acetyl-CoA C-2 (AC2) and in Figure 5B for reactions involving acetyl-CoA C-1 (Ac ). Consequently, these reaction schemes illustrate the sequential formation of multiply-labeled intermediates, where C refers to citrate, K to a-ketoglutarate (which in the steady... 

Take for example the intracellular degradation of PHB, a simplified mechanism can be observed in the scheme shown in the Fig. 5. This mechanism begins by the hydrolysis of chain polymer catalyzed by a i-PHB depolymerase leads to (/ )-3HB-CoA (1), after a 3HB dehydrogenase converts the (/ )-3HB-CoA to acetoacetyl-CoA (2) and a 3-ketoacyl-CoA thiolase converts the acetoacetyl-CoA to acetyl-CoA (3). After that, under aerobic conditions, the acetyl-CoA enters in the citric acid cycle and is oxidized to CO2 (Eggers and Steinbuchel 2013 Jendrossek and Handrick 2002 Lenz and Marchessault 2(X)5 Philip et al. 2007 Senior and Dawes 1973). 

According to the authors the formulation shown in Fig. 4A requires that the carboxylate ion be bound to the enzyme so that complete randomization between all three carbons is prohibited. In the above scheme randomization between the a- and 8-carbons would be complete with propionate where racemization is obligatory. In the case of lactate, however, use of the DL-substrate would only result in a partial randomization since the withdrawal of the D-isomer via pyruvate and the citric acid cycle would compete with the route leading to its inversion. 

This scheme is that acetate may condense with a-ketoglutarate to yield a homolog of citric acid, which, by undergoing a series of reactions analogous to the citric acid cycle, should yield homoisocitrate, oxalo-glutarate, a-ketoadipate, and ultimately, a-aminoadipic acid. 

Formation of a poly-j -keto-acyl-CoA [as (5.9)] occurs as for fatty acid biosynthesis by condensation of acetyl-coenzyme A with malonyl-CoA. Malonyl-CoA is generally derived by carboxylation of 3.1) (Scheme 3.3). An alternative path to malonyl-CoA is via oxaloacetate, an intermediate in the citric acid cycle. 

Once the structure of acetyl CoA was known, a detailed chemical scheme of fatty-acid oxidation could be formulated, based on several experimental observations published in the literature. I presented it in my first publication on acetyl CoA i and called it later the fatty acid cycle .< The substrate is regenerated in this repeated reaction sequence, which thus resembles the citric acid cycle or the cyclic process in the synthesis of urea. In these other cyclic processes, however, identical substrates are formed after each cycle, whereas a shorter homologous chain is formed in each repetition of the fatty acid cycle . It would therefore be more appropriate to describe the oxidation of fatty acids by a spiral process rather than by a cycle. 

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